It became known in recent years that nucleosides show a variety of physiological activities, and many natural and nonnatural nucleosides have been synthesized. Of these, 3'-deoxy-3'-fluorothymidine has drawn attention because of its activity against the virus causing AIDS, and the following four methods have been disclosed for the production of this compound.
(1) 3'-Mesylthymidine or 2,3'-anhydrothymidine is allowed to react with potassium hydrogen fluoride or ammonium fluoride in ethylene glycol at 191.degree. C. for 10 to 90 minutes, thus giving 3'-deoxy-3'-fluorothymidine (yield: 10 to 14%) [Japanese Patent Publication No. 10472 (1973)]. PA0 (2) Reaction of thymidine with 4-chlorobenzoyl chloride in pyridine at 5.degree. to 20.degree. C. forms 5'-(4-chlorobenzoyl)thymidine (yield: 80%), which is then allowed to react with diethylaminosulfur trifluoride in methylene chloride at -78.degree. C., thus giving 3'-deoxy-3'-fluorothymidine (yield: 19.9%) [Japanese Patent Kokai No. 68325 (1989)]. PA0 (3) Reaction of 2,3'-anhydro-5'-mesylthymidine with hydrogen fluoride in triethylamine at 150.degree. C. for 90 minutes gives a mixture of 3'-deoxy-3'-fluorothymidine and 3'-deoxy-3'-fluoro-5'-mesylthymidine (yield: 19%) [Zeitschrift fur Chemie, 23, 335 (1983)]. PA0 (4) Reaction of 2,3'-anhydro-5'-mesylthymidine with hydrogen fluoride and aluminum fluoride in dioxane at 170.degree. C. forms 3'-deoxy-3'-fluoro-5'-mesylthymidine (yield: 61%), which is then demesylated by the use of sodium hydroxide, thus giving 3'-deoxy-3'-fluorothymidine (yield: 46%) [Journal fur Praktische Chemie, 315, 895 (1973)].
Any of these methods is not satisfactory as an industrial process, because the product yield is low, an expensive reagent has to be used, the reproducibility is low, or it is not easy to obtain the purified product.
Another synthetic method is also known, in which, after protecting the 5'-hydroxyl group in thymidine with mesyl group (an acid-resistant protective group), the 3'-position is fluorinated by the use of hydrogen fluoride to form 3'-deoxy-3'-fluoro-5'-mesylthymidine (hereinafter abbreviated as "5'-mesyl derivative"), followed by demesylation, thus giving 3'-deoxy-3'-fluorothymidine. The demesylation reaction, which is a step in this synthetic method, is generally carried out under alkaline conditions by the use of an alkali hydroxide, but this method is not applicable to the 5'-mesyl derivative because it contains a fluorine atom which is reactive with an alkali hydroxide. Hence, a method is used in this case, in which the mesyl group is first substituted with acetyl group by reaction with potassium acetate in acetic anhydride, and 5'-acetyl-3'-deoxy-3'-fluorothymidine thus formed (hereinafter abbreviated as "5'-acetyl derivative") is deacetylated, thus giving 3'-deoxy-3'-fluorothymidine [Nucleic Acid Chemistry, Part I, on pages 299-302 (1978)].
This acetylation reaction requires the use of acetic anhydride in an amount of about 100 times as much as that of the 5'-mesyl derivative and heating for a long time, entailing excessively colored reaction products, a large amount of by-products, and a very low yield of the 5'-acetyl derivative. Hence, column chromatography of low efficiency has to be used for purification, making it difficult to industrially produce the 5'-acetyl derivative in large quantities.